Letters in Organic Chemistry - Volume 16, Issue 5, 2019

The structural diversity of spiro heterocycles has achieved an extensive attention of organic chemists due to their vast synthetic applications. Among these, spiropyrazolines are gaining considerable prominence due to their biological and pharmacological activities, electrophotographic photosensitivity as well as their application as beneficial synthons for spirocyclopropanes, cyclobutanes, pyrrolidinones, pyrazoles, 3-amino oxindoles and several natural products molecular architecture. In view of all these, this review aims to provide the classical and advanced regioselective approaches as well as synthetic applications of spiropyrazolines. The key reactions for its synthesis are 1,3-dipolar cycloaddition and condensations that are described completely in this piece of work.

The mechanism of addition of nucleophiles to the π-acid complexed alkynes has been studied successfully by the assessment of energy of intermediates and activation parameters. To elucidate the origin of stereoselectivity and predict the reaction pathways, the geometry optimizations of reactants, products, intermediates and transition states, were calculated by using density functional theory (DFT) at the B3LYP/6-31+G(d) method. The reaction mechanism of hydration of alkynes in the catalyzed synthesis of bis-spiroketal by DFT calculations is explored. The pyranyl enol ether was formed regioselectively by the first ring closure. Further, bis-enol ether was formed by second 6-exodig addition. Then, dehydration, followed by dehydrative ring closure finally gave bis-spiroketal product. It is concluded that one of the most feasible reaction pathways comprises pyranyl enol ether and bis-enol ether formation as intermediates. The final cyclization step of product formation is endothermic. In terms of stereochemistry, the trans-product is found to be energetically more stable than cisproduct and hence supports the electivity of the reaction.

We developed a series of new hydrotalcite functionalized Ru catalytic system to synthesize formic acid via CO2 hydrogenation reaction. Advance analytical procedures like FTIR, N2 physisorption, ICP-OES, XPS, and TEM analysis were applied to understand the physiochemical nature of functionalized hydrotalcite materials. This well-analyzed system was used as catalysts for CO2 hydrogenation reaction (with and without ionic liquid medium). Ru metal containing functionalized hydrotalcite materials were found highly active catalysts for formic acid synthesis via hydrogenation reaction. The concern of catalyst stability was studied via catalysts leaching and recycling experiments. We recycled the ionic liquid mediated functionalized hydrotalcite catalytic system up to 8 runs without any significant loss of catalytic activity. Surprisingly, no sign of catalyst leaching was recorded during the catalyst recycling experiment.

Scale-up fermentation of the endophytic fungus Penicillium chrysogenum in biomaltpeptone media followed by cytotoxicity-guided fractionation led to the isolation of haenamindole, an unusual diketopiperazine (DKP) alkaloid, along with other five known DKPs. Haenamindole was elucidated on the basis of comprehensive 1D and 2D NMR spectroscopic including 15N-HSQC and 15NHMBC and mass spectrometric analyses. The compound possesses the secondary hydroxamic acid functionality of N-piperazindione ring system confirmed by methylation in sodium dimethyl sulfate and dry dimethylformamide to yield haenamindole-22-N-methyl ether. However, haenamindole demonstrated weak HCV protease activity with an IC50 value of 76.3μM, its cytotoxicity profiling in a panel of up to 12 cell lines indicated significant cytotoxicity of the compound with pronounced selectivity for colon-38 cancer cells compared to the human normal cells.

5-bromo-2-(prop-2-yn-1-yloxy)benzaldehyde (compound 3) and 3,5-di-tert-butyl-2-(prop-2- yn-1-yloxy)benzaldehyde (compound 5) were synthesized via nucleophilic substitution reactions. Compound 5 showed higher antioxidant capacity with respect to compound 3 in all the four different antioxidant activity methods used. Moreover, in phosphomolybdenum assay, compound 5, with 1.1 proportion value, showed almost the same total antioxidant capacity compared to universal trolox standard. Furthermore, Broth microdilution method and agar disc diffusion tests demonstrated that the same compound also exhibited good antibacterial activity towards the bacteria Bacillus subtilis. Finally, both of the benzaldehyde compounds showed high antifungal activity against Aspergillus niger. In this study, compound 5 (IC50: 54.3 μg/ml) showed significant cytotoxic activity against breast adenocarcinoma cell line MCF-7 with respect to compound 3 (IC50: 173.4 μg/ml).

Pyrazine, a kojic acid having hydroxypyrone, and hydroquinone are the head compounds of different categories possessing a broad range of biological activities including anticancer and antioxidant activities, thus are interested in evaluating the cytotoxicity on K562 human leukemia cells and radical scavenging activities of these compounds in bonding together as ester compounds. Four hydroxypyrone containing-2-pyrazinoic esters along with hydroquinone containing-one were synthesized and characterized by spectral data. The cytotoxicity of these compounds on K562 human leukemia cells and free Radical scavenging activities were evaluated. The K562 cells were treated with various concentrations of each compound for a different time and cell viabilities were determined by MTT viability assay. It was observed that all compounds decreased the viability of the human leukemia K562 cells in a dose- and time-dependent manner. Hydroquinone pyrazinoate 4a with an IC50 value of 50±8.0 μM was the most active compound against the K562 cells. The compounds 4b and 4e showed higher cytotoxicity on K562 cells respectively after 72 h. Antioxidant activities of the compounds were evaluated by DPPH free radical scavenging assay. Hydroquinone ester 4a showed higher activity with an IC50 value of 0.82 mM than those of hydroxypyrone derivatives of which maltol pyrazinoate 4e showed the highest inhibition with IC50 value of 4.7 mM. Although free hydroxyl group of kojic acid was masked by ester group, 4b and 4e showed significant scavenging activities, as the same result was observed in the case of hydroquinone ester.

A series of biologically active 3-quinoline carboxylic acid hydrazide-hydrazones has been synthesized from 3-quinoline carboxylic acid hydrazide and a variety of aldehydes, with moderate to good yields. The chemical structures of the new products were confirmed by elemental analysis, IR, and 1H NMR, 13C NMR spectral data. The structural and frontier molecular orbital (FMO) properties and the density functional theory (DFT) calculations were conducted for the new compounds. The new hydrazide-hydrazones exhibited low to moderate antibacterial activity against Staphylococcus aureus and Esherichia coli in comparison with gentamycin. Among the tested compounds, compounds 9 and 13 were found to be the most active. Phthalimide derivative 2 of 3-quioline carboxylic acid hydrazide showed remarkable antibacterial activity.

One of the major challenges facing modern biochemical and biomedical technologies are finding molecular tools for diagnosis and detection of genetic diseases. In this connection, several classes of oligonucleotides have been developed that can recognize and bind to DNA and RNA with high affinity and sequence selectivity and withstand enzymatic degradation by proteases and nucleases; however, few can traverse the cell membrane on their own. One such promising class of nucleic acid mimics developed in the last two decades which showed good results in vitro, are the peptide nucleic acids (PNAs). New chiral α- and γ-peptide Nucleic Acid (PNA) submonomer with methyl substituents in pseudopeptide backbone were synthesized via Mitsunobu reaction. The α-(R)-/γ-(S)-configuration of the chiral centres will ensure the preorganization of the PNA oligomer into a right-handed helix. The results obtained showed that Boc/Fmoc-submonomer compatible with Boc-protocol PNAs solid-phase synthesis on an MBHA resin. We synthesized simple and efficient α-R-, γ-S-disubstituted PNA submonomer based on L-Ala and D-Ala with the construction of the intermediate pseudopeptide moiety by Mitsunobu reaction for subsequent use in the Boc-Protocol of solid phase PNA synthesis.